EP1621536A1 - Dérivés d'urées cycliques aminés, leur préparation et utilisation pharmaceutique en tant qu'inhibiteurs de Kinase - Google Patents

Dérivés d'urées cycliques aminés, leur préparation et utilisation pharmaceutique en tant qu'inhibiteurs de Kinase Download PDF

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Publication number
EP1621536A1
EP1621536A1 EP04291904A EP04291904A EP1621536A1 EP 1621536 A1 EP1621536 A1 EP 1621536A1 EP 04291904 A EP04291904 A EP 04291904A EP 04291904 A EP04291904 A EP 04291904A EP 1621536 A1 EP1621536 A1 EP 1621536A1
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EP
European Patent Office
Prior art keywords
chosen
different
ylmethyl
dimethyl
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04291904A
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German (de)
English (en)
Inventor
Hartmut Strobel
Conception Nemecek
Dominique Lesuisse
Sven Ruf
Youssef El-Ahmad
Stefan Guessregen
Anne Lebrun
Kurt Ritter
Didier Benard
Augustin Hittinger
Hervé Bouchard
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Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
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Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Priority to EP04291904A priority Critical patent/EP1621536A1/fr
Priority to CNA2005800250805A priority patent/CN101031559A/zh
Priority to DE602005026395T priority patent/DE602005026395D1/de
Priority to PCT/EP2005/008720 priority patent/WO2006010641A2/fr
Priority to BRPI0512681-9A priority patent/BRPI0512681A/pt
Priority to AU2005266460A priority patent/AU2005266460A1/en
Priority to EA200700141A priority patent/EA011088B1/ru
Priority to CA002571323A priority patent/CA2571323A1/fr
Priority to AT05771072T priority patent/ATE498618T1/de
Priority to MX2007001024A priority patent/MX2007001024A/es
Priority to JP2007523038A priority patent/JP2008508228A/ja
Priority to EP05771072A priority patent/EP1773808B1/fr
Priority to KR1020077002102A priority patent/KR20070038529A/ko
Priority to ARP050103075A priority patent/AR050269A1/es
Priority to PE2005000866A priority patent/PE20060383A1/es
Priority to TW094125192A priority patent/TW200616973A/zh
Priority to UY29039A priority patent/UY29039A1/es
Publication of EP1621536A1 publication Critical patent/EP1621536A1/fr
Priority to IL180286A priority patent/IL180286A0/en
Priority to MA29602A priority patent/MA28732B1/fr
Priority to US11/627,518 priority patent/US7759379B2/en
Priority to NO20071067A priority patent/NO20071067L/no
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel amino cyclic urea derivatives, to a process for preparing them, to their use as medicinal products, to pharmaceutical compositions containing them and to the pharmaceutical use of such derivatives for preventing and treating complaints that may be modulated by inhibiting the activity of protein kinases.
  • the present invention relates to novel amino cyclic urea derivatives that have inhibitory effects on protein kinases.
  • the products of the present invention may thus be used especially for preventing or treating complaints capable of being modulated by inhibiting the activity of protein kinases.
  • the inhibition and regulation of protein kinases especially constitute a powerful new mechanism of action for treating a large number of solid tumours.
  • Such protein kinases belong especially to the following group:
  • the protein kinase IGF1-R (Insulin Growth Factor-1 Receptor) is particularly indicated.
  • the protein kinase FAK is also indicated.
  • the protein kinase AKT is also indicated.
  • the present invention thus relates particularly to novel inhibitors of the IGF-1R receptor that may be used for oncology treatments.
  • the present invention also relates to novel FAK receptor inhibitors that may be used for oncology treatments.
  • the present invention also relates to novel AKT receptor inhibitors that may be used for oncology treatments.
  • Cancer remains a disease for which the existing treatments are clearly insufficient.
  • Certain protein kinases especially including IGF-1R (Insulin Growth Factor 1 Receptor), play an important role in many cancers.
  • the inhibition of such protein kinases is potentially important in the chemotherapy of cancers, especially for suppressing the growth or survival of tumours.
  • the present invention thus relates to the identification of novel products that inhibit such protein kinases.
  • Protein kinases participate in signalling events that control the activation, growth and differentiation of cells in response either to extracellular mediators or to changes in the environment. In general, these kinases belong to two groups: those that preferentially phosphorylate serine and/or threonine residues and those that preferentially phosphorylate tyrosine residues [S.K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576-596].
  • the serine/threonine kinases are, for example, the isoforms of the protein kinases C [A.C. Newton, J. Biol.
  • Tyrosine kinases comprise growth factor receptors, for instance the epidermal growth factor (EGF) receptor [S. Iwashita and M. Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosol kinases, for instance p56tck, p59fYn and ZAP-70 and the kinases csk [C. Chan et. al., Ann. Rev. Immunol., 1994, 12, pages 555-592].
  • EGF epidermal growth factor
  • kinase protein activity has been implicated in many diseases, resulting from abnormal cellular functions. This may arise either directly or indirectly from a dysfunction in the mechanisms for controlling the kinase activity, linked, for example, to a mutation, an overexpression or an inappropriate activation of the enzyme, or an over- or underproduction of cytokines or of growth factors, also involved in the transduction of the signals upstream or downstream of the kinases. In all these cases, a selective inhibition of the action of the kinases offers hope of a beneficial effect.
  • the type 1 receptor for the insulin-like growth factor is a transmembrane receptor with tyrosine kinase activity which binds firstly to IGFI, but also to IGFII and to insulin with lower affinity.
  • the binding of IGF1 to its receptor results in oligomerization of the receptor, the activation of tyrosine kinase, intermolecular autophosphorylation and the phosphorylation of cell substrates (main substrates: IRS1 and Shc).
  • the receptor activated by its ligand induces mitogenic activity in normal cells.
  • IGF-I-R plays an important role in "abnormal" growth.
  • IGF-I-R is often found overexpressed in many types of tumour (breast, colon, lung, sarcoma, etc.) and its presence is often associated with a more aggressive phenotype.
  • High concentrations of circulating IGF1 are strongly correlated with a risk of prostate cancer, lung cancer and breast cancer.
  • IGF-I-R is necessary for establishing and maintaining the transformed phenotype in vitro as in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6].
  • the kinase activity of IGF-I-R is essential for the transformation activity of several oncogenes: EGFR, PDGFR, the large T antigen of the SV40 virus, activated Ras, Raf, and v-Src.
  • the expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which may then result in the formation of a tumour in vivo.
  • the expression of IGF-I-R plays an important role in substrate-independent growth.
  • IGF-I-R has also been shown to be a protector in chemotherapy-induced and radiation-induced apoptosis, and cytokine-induced apoptosis. Furthermore, the inhibition of endogenous IGF-I-R with a negative dominant, the formation of a triple helix or the expression of an antisense sequence brings about suppression of the transforming activity in vitro and reduction of tumour growth in animal models.
  • FAK Fluorescence Adhesion Kinase
  • FAK is a cytoplasmic tyrosine kinase that plays an important role in transducing the signal transmitted by the integrins, a family of heterodimeric receptors of cellular adhesion.
  • FAK and the integrins are colocalized in perimembrane structures known as adhesion plaques. It has been shown in many cell types that the activation of FAK and its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397 were dependent on the binding of the integrins to their extracellular ligands and thus induced during cellular adhesion [Kornberg L, et al. J. Biol. Chem. 267(33): 23439-442 (1992)].
  • the autophosphorylation on tyrosine 397 of FAK represents a binding site for another tyrosine kinase, Src, via its SH2 domain [Schaller et al. Mol. Cell. Biol. 14: 1680-1688 1994; Xing et al. Mol. Cell. Biol. 5: 413-421 1994].
  • Src can then phosphorylate FAK on tyrosine 925, thus recruiting the adapter protein Grb2 and inducing in certain cells activation of the ras and MAP kinase pathway involved in controlling cellular proliferation [Schlaepfer et al. Nature; 372: 786-791 1994; Schlaepfer et al. Prog. Biophy. Mol. Biol. 71: 435-478 1999; Schlaepfer and Hunter, J. Biol. Chem. 272: 13189-13195 1997].
  • PI3-kinase Phosphatidylinositol-3-OH kinase
  • the FAK/Src complex phosphorylates various substrates, for instance paxillin and p130CAS in fibroblasts [Vuori et al. Mol. Cell. Biol. 16: 2606-2613 1996].
  • fibroblasts that are deficient for the expression of FAK show a rounded morphology and deficiencies in cell migration in response to chemotactic signals, and these defects are suppressed by reexpression of FAK [DJ. Sieg et al., J. Cell Science. 112: 2677-91 1999].
  • the overexpression of the C-terminal domain of FAK (FRNK) blocks the stretching of adherent cells and reduces cellular migration in vitro [Richardson A. and Parsons J.T. Nature. 380 : 538-540 1996].
  • the overexpression of FAK in CHO or COS cells or in human astrocytoma cells promotes migration of the cells.
  • Protein kinase AKT also known as PKB
  • PI3K phosphoinositide 3-kinase
  • AKT serine/threonine kinase
  • hypoxia modulates the induction of VEGF in cells transformed with Ha-ras by activating the PI3K/AKT pathway and by involving the binding sequence of the HIF-1 (hypoxia inducible factor-1) transcription factor known as HRE for "hypoxy-responsive element”.
  • HIF-1 hypoxia inducible factor-1
  • AKT plays a very important role in cancer pathologies.
  • the amplification and/or overexpression of AKT has been reported in many human tumours, for instance gastric carcinoma (amplification of AKT1), ovary carcinomas, breast carcinoma or pancreatic carcinoma (amplification and overexpression of AKT2) and breast carcinomas deficient in oestrogen receptors, and also androgen-independent prostate carcinomas (overexpression of AKT3).
  • AKT is constitutively activated in all the PTEN tumours, the PTEN phosphatase being deleted or inactivated by mutations in many types of tumours, for instance carcinomas of the ovary, of the prostate, of the endometrium, glioblastomas and melanomas.
  • AKT is also involved in the oncogenic activation of bcr-abl (references: Khawaja A., Nature 1999, 401, 33-34; Cardone et al. Nature 1998, 282, 1318-1321; Kitada S. et al., Am J Pathol 1998 Jan; 152(1): 51-61; Mazure NM et al. Blood 1997, 90, 3322-3331; Zhong H. et al. Cancer Res. 2000, 60, 1541-1545).
  • One subject of the present invention is thus the products of general formula (I): in which:
  • the radical NR1R2 is such that :
  • alkyl radicals containing not more than 6 carbon atoms and especially methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, linear or branched pentyl and linear or branched hexyl radicals.
  • alkenyl values that may be mentioned more particularly are the values allyl or butenyl.
  • alkynyl values that are mentioned more particularly is the propargyl value.
  • Heterocycloalkyl radicals that may especially be mentioned include dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, morpholinyl, or tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidyl, perhydropyranyl, pyrindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and thioazolidinyl radicals, all these radicals being optionally substituted.
  • heterocycloalkyl radicals that may especially be mentioned are optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl and thioazolidinyl radicals: mention may also be made more particularly of optionally substituted morpholinyl, pyrrolidyl and piperazinyl radicals;
  • 6-membered heteroaryl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, and pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrazolyl radicals;
  • fused heteroaryl radicals that may be mentioned more particularly are benzothienyl, benzofuranyl, indolyl, quinolyl, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, 1,3,4-thiadiazolyl, thiazolyl and thienyl radicals and triazolyl groups, these radicals optionally being substituted as indicated for the heteroaryl radicals;
  • patient denotes human beings, but also other mammals.
  • prodrug denotes a product that may be converted in vivo via metabolic mechanisms (such as hydrolysis) into a product of formula (I).
  • metabolic mechanisms such as hydrolysis
  • an ester of a product of formula (I) containing a hydroxyl group may be converted by hydrolysis in vivo into its parent molecule.
  • an ester of a product of formula (I) containing a carboxyl group may be converted by in vivo hydrolysis into its parent molecule.
  • esters of the products of formula (I) containing a hydroxyl group include the acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylenebis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-tolyltartrates, methanesulphonates, ethanesulphonates, benzene-sulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • Esters of products of formula (I) that are particularly useful, containing a hydroxyl group may be prepared from acid residues such as those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507: these esters especially include substituted (aminomethyl)benzoates, dialkylaminomethylbenzoates in which the two alkyl groups may be linked together or may be interrupted with an oxygen atom or with an optionally substituted nitrogen atom, i.e. an alkylated nitrogen atom, or alternatively (morpholinomethyl)benzoates, e.g. 3- or 4-(morpholinomethyl)benzoates, and (4-alkyl-piperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
  • substituted (aminomethyl)benzoates dialkylaminomethylbenzoates in which the two alkyl groups may be linked together or may be interrupted with an oxygen
  • the carboxyl radical(s) of the products of formula (I) may be salified or esterified with various groups known to those skilled in the art, among which nonlimiting examples that may be mentioned include the following compounds:
  • esterified carboxyl means, for example, radicals such as alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.
  • radicals formed with readily cleavable ester residues such as methoxymethyl or ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, and isopropyloxycarbonyloxy methyl or ethyl radicals.
  • ester radicals may be found, for example, in European patent EP 0 034 536.
  • aminoated carboxyl means radicals of the type -CONRxRy in which the amino radicals -NRxRy have the meanings given above: especially, Rx and Ry, which may be identical or different, represent a hydrogen atom, a cyclic radical as defined above or below or an alkyl radical containing from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals and especially amino, alkylamino and dialkylamino radicals, all these cyclic and alkyl radicals being optionally substituted.
  • alkylamino radical means, for example, linear or branched methylamino, ethylamino, propylamino or butylamino radicals. Alkyl radicals containing not more than 4 carbon atoms are preferred, the alkyl radicals possibly being chosen from the alkyl radicals mentioned above.
  • dialkylamino radical means, for example, dimethylamino, diethylamino and methylethylamino radicals. As previously, alkyl radicals containing not more than 4 carbon atoms, chosen from the list indicated above, are preferred.
  • salts formed for example, with one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine. The sodium salt is preferred.
  • the addition salts with mineral or organic acids of the products of formula (I) may be, for example, the salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulphuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkylmonosulphonic acids such as, for example, methanesulphonic acid, ethanesulphonic acid or propanesulphonic acid, alkyldisulphonic acids such as, for example, methanedisulphonic acid or ⁇ , ⁇ -ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid, and aryldisulphonic acids.
  • hydrochloric acid hydrobromic acid
  • stereoisomerism may be defined in its broad sense as the isomerism of compounds having the same structural formulae but whose various groups are arranged differently in space, especially such as in monosubstituted cyclohexanes whose substituent may be in an axial or equatorial position, and the various possible rotational conformations of ethane derivatives.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often referred to as geometrical isomerism or cis-trans isomerism.
  • the term "stereoisomer" is used in the present patent application in its broadest sense and thus relates to all the compounds indicated above.
  • a subject of the present invention is thus the products of general formula (I) as defined above in which A represents a phenyl or heteroaryl radical or a monocyclic or bicyclic fused carbocyclic or heterocyclic 5- to 11-membered radical, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R3, with R3 and the other substituents of the said products of formula (I) being chosen from the values defined for R3 and for the said substituents, the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • One subject of the present invention is thus the products of general formula (I) as defined above in which L1 represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or several substituents chosen from the values of R7, with R7 and the other substituents of the said products of formula (I) being chosen from all the values defined for R7 and for the substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • R3 represents a hydrogen atom, a halogen atom; an alkyl, cycloalkyl, alkoxy or alkylenedioxy radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; -NR13R14; -C(O)R13; -S(O) n R13; -C(O)NR15R16; -S(O) n NR15R16; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8; with R7, R8, R13, R14, R15 and R16 and the other substituents of the said products of formula (I) being chosen from all the values defined for R7, R8, R13, R14, R15 and R16 and for the said substituents, the said products of formula (I)
  • a subject of the present invention is thus the products of general formula (I) as defined above, in which R4 represents a hydrogen atom, a halogen atom (F), an alkyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; it being understood that two substituents R4 may form, with the carbon atom(s) to which they are attached, a 3- to 7-membered ring optionally containing one or more hetero atoms, which may be identical or different, chosen from O, S, N and N-alkyl; with R7 and the other substituents of the said products of formula (I) being chosen from all the values defined for R7 and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • R4 represents
  • the ring formed is especially a cycloalkyl radical containing from 3 to 6 carbon atoms, and more particularly a cyclopropyl radical; the other substituents of the said products of formula (I) being chosen from all the values defined for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • One subject of the present invention is thus the products of general formula (I) as defined above in which L2 is chosen from a single bond and an alkylene, cycloalkylene, -O- or -NR17- radical, the other substituents of the said products of formula (I) being chosen from all the values defined for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • a subject of the present invention is thus the products of general formula (I) as defined above in which Y represents an N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from O, S and N and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; with R5 and the other substituents of the said products of formula (I) being chosen from all the values defined for R5 and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • a subject of the present invention is thus the products of general formula (I) as defined above, in which R5 more particularly represents a hydrogen atom, a halogen atom or an alkyl, cycloalkyl, -NHR20, -NHCOR20, -NHCONR19R20 or -NH-S(O)2-R20 radical; R5 even more particularly represents a hydrogen atom, a halogen atom; an alkyl, cycloalkyl, NH2, -NH-cycloalkyl, -NHCO-alkyl, -NHCO-cycloalkyl, -NHCONH-alkyl or -NHCON(dialkyl) radical, the alkyl and cycloalkyl residues being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms (F) and alkoxy, morpholinyl, piperidyl, piperazinyl, N-methylpiperazinyl and COOH radicals;
  • a subject of the present invention is thus, particularly, the products of formula (I) as defined above corresponding to formula (Ia): in which:
  • a subject of the invention is especially the products of formula (I) as defined above such that p represents the integer 0, the other substituents of the said products of formula (I) each having any one of the values defined in the present invention.
  • a subject of the invention is especially the products of formula (I) as defined above such that p represents the integer 1, the other substituents of the said products of formula (I) having any one of the values defined in the present invention.
  • a subject of the invention is especially the products of formula (I) as defined above such that p represents the integer 2, the other substituents of the said products of formula (I) having the values defined in the present invention.
  • a subject of the present invention is, more particularly, the products of formula (I) or (Ia) as defined above corresponding to formula (Ib):
  • Ab represents phenyl, heteroaryl or a carbocyclic or heterocyclic 7- to 11-membered cyclic radical, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R3b;
  • Xb represents a single bond or the following divalent radicals: -N (R6b) -; -O-; -C(O)-; -S (O) n-; -N (R6b) -C (O) - and -N(R6b)-SO2-;
  • L1b represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals;
  • the radical NR1bR2b is such that:
  • a subject of the present invention is, even more particularly, the products of formula (I), (Ia) or (Ib) as defined above, corresponding to formula (Ic): in which A represents a phenyl, a 5 to 6-membered heteroaryl or a condensed heterocyclic ring system selected from the list: 1,2,3,4-tetrahydro-quinolin, 1,2,3,4-tetrahydro-isoquinolin, indolyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-benzothiazole, tetrahydroquinoline or tetrahydroisoquinoline; all these radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from alkyl, alkoxy, cycloalkyl, alkylamino and dialkylamino radicals, each alkyl radical being optionally substituted with one or
  • a subject of the present invention is, most particularly, the products of formula (I) as defined above corresponding to formula (Id): in which:
  • R1d and R2d are especially such that:
  • a subject of the present invention is especially the products of formula (I), (Ia), (Ib), (Ic) or (Id) as defined above in which, when A represents a phenyl radical, then X represents -O-, -NR6 or -NH-CO, the other substituents of the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being chosen from all the values defined for the said substituents, the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I), (Ia), (Ib), (Ic) or (Id).
  • a subject of the present invention is also especially the products of formula (I), (Ia), (Ib), (Ic) or (Id) as defined above in which, A represents an indolinyl radical, X represents -O-, -NR6, -CO- or -NR6-CO and the other substituents of the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being chosen from all the values defined for the said substituents, the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I), (Ia), (Ib), (Ic) or (Id).
  • a subject of the present invention is, more specifically, the products of formula (I) as defined above, the names of which are given hereinbelow:
  • an intermediate of general formula 1a in which the variables have the abovementioned meanings and in which X' denotes NH2, OH or SH, is reacted with a difunctional alkylating agent of general formula 1b, for instance a haloalkanal acetal.
  • a difunctional alkylating agent of general formula 1b for instance a haloalkanal acetal.
  • the reaction is performed in bulk or in an inert organic solvent, optionally in the presence of a base.
  • a preferred alkylating agent is bromoacetaldehyde diethyl acetal.
  • One variant for access to I describes the direct alkylation of compounds of general formula la with an aminoalkyl halide of general formula Hal-L 1 -N(R1R2).
  • this reaction is preferably performed in an organic solvent such as ethyl acetate, DMF, NMP or acetone, in the presence of a base such as potassium tert-butoxide, potassium carbonate or caesium carbonate.
  • a base such as potassium tert-butoxide, potassium carbonate or caesium carbonate.
  • X' denotes NH2
  • the process preferably proceeds first with acylation and the intermediate amide is used for the alkylation.
  • Preferred acyl radicals are acetyl and trifluoroacetyl. Removal of the acyl group once the alkylation has been performed then gives rise to compounds according to the invention, which may be optionally converted into compounds of general formula Ic via additional steps.
  • a suitably substituted nitroaniline which may be obtained, for example, by nitration of the corresponding aniline, is, in the present case, converted into the corresponding isocyanate or into a derivative of similar reactivity, in an inert solvent under the action of phosgene, diphosgene, triphosgene or carbonyldiimidazole, in the presence or absence of an auxiliary base, and reacted with a compound of general formula 2a to give rise to the heterocyclic compounds of general formula 2b.
  • 2a are preferably obtained by reductive amination of the corresponding amino acid derivative with an aldehyde of general formula R5-Y-L 2 ' -CHO.
  • the intermediates of general formula 1a may also be prepared by direct nitration of compounds of general formula 2c.
  • the subsequent reduction of the nitro compound 2b is performed by catalytic hydrogenation in the presence of a heterogeneous or homogeneous transition metal catalyst, preferably a heterogeneous transition metal catalyst.
  • a heterogeneous or homogeneous transition metal catalyst preferably a heterogeneous transition metal catalyst.
  • the reduction may also be performed with a non-precious metal in the presence of an acid.
  • Preferred reagents for this reaction are zinc and dilute hydrochloric acid, particularly preferably zinc and glacial acetic acid.
  • the reaction temperature is preferably between room temperature and the reflux point of the solvent, particularly preferably at the reflux point.
  • the cyclization may also be performed in aqueous-acidic solution at elevated temperature.
  • One variant of the process for preparing the compounds of general formulae Ia, Ib and Ic, in which X' denotes NR6, O or S, consists in converting the constituent components of general formulae 3a-d into the corresponding isocyanate or into a derivative of similar reactivity, with phosgene, diphosgene, triphosgene or carbonyldiimidazole, in the presence or absence of an auxiliary base, and in then reacting them with an amino acid derivative of general formula 2a under the conditions mentioned for the preparation of 1a.
  • the intermediates thus obtained are then converted into compounds of general formulae Ia-c in a manner similar to that for the reactions described in Scheme 1.
  • the arylamines 3a are in part described in the literature or may be obtained in accordance with conversions known to those skilled in the art from derivatives known in the literature.
  • the starting substances 3b-e are obtained from 3a via synthetic routes that are in principle similar to the reaction sequences described in Scheme 1.
  • the free amino group is, in the present case, protected with the usual protecting groups or masked in the form of a nitro function, and reduced at a subsequent stage.
  • Preferred reagents are chloroacetyl chloride, acryloyl chloride, 2-chloropropionyl chloride and chloromethanesulphonyl chloride, and also homologues thereof.
  • the coupling is preferably performed in an inert solvent at low temperature.
  • the use of a base is optional.
  • the compounds of general formula Id are obtained by reaction with a suitably substituted amine. This reaction may be performed in an inert organic solvent or in bulk, optionally in the presence of an auxiliary base.
  • aminopropionylamides according to the invention are obtained after reaction with amines.
  • 4a may also be reacted directly with amino-substituted difunctional reagents of general formula 4b to give rise to compounds of general formula Id.
  • the compounds of general formula I in which X denotes -N(R6)-C(O)- and R2 and L1 form a nucleus are obtained by reacting compounds of general formula 4a with an activated amino acid derivative of general formula 5.
  • the amino acid may be activated by conversion into the acid chloride or via amide coupling reactions that are sufficiently known to those skilled in the art.
  • the products initially obtained, Ie may be converted into other compounds Ie according to the invention via other conversions.
  • the compounds of general formula I in which X' denotes -C(O)-N(R6)-, -S02-NR6- or -C(O)O-, are obtained in accordance with Scheme 5.
  • the intermediates 6b in which -T denotes -COOH, -COO-Alkyl, -S020H, -SO2Cl or -S02F, are, in the present case, prepared by a reaction sequence as has just been described in Scheme 2.
  • the compounds 6a are commercially available or may be prepared from commercially available derivatives via conversions known to those skilled in the art.
  • 6b is first activated by the action of agents such as, for example, thionyl chloride, oxalyl chloride or phosphorus pentachloride.
  • agents such as, for example, thionyl chloride, oxalyl chloride or phosphorus pentachloride.
  • the activation may also be performed with coupling agents known to those skilled in the art, for instance TOTU or DCC.
  • Scheme 6 illustrates, by way of example, the way in which compounds in which A denotes a system containing a fused homocyclic or heterocyclic nucleus may be prepared.
  • nucleus A is first linked to the central heterocycle in accordance with the reaction sequence described for compound 2b.
  • the compounds of general formula I are then obtained by alkylation, acylation, sulphonylation, carbamoylation or thiocarbamoylation and additional reactions of the derivatives thus obtained.
  • the compounds of general formula I may moreover be obtained by reacting an amino acid derivative of general formula 7a with an isocyanate 7b or an analogue of similar reactivity, in which Z denotes a group A-, R3A-or R3A(X')- or denotes
  • the intermediates 7c formed are then converted into compounds of general formula I by alkylation with a halide Hal-L 2 -Y-R5 or another reagent of similar reactivity.
  • the alkylation reactions are preferably performed in an organic solvent, for instance dimethylformamide, N-methylpyrrolidone, ethyl acetate or acetone, in the presence of a base, for instance potassium carbonate, caesium carbonate, sodium hydride or potassium tert-butoxide.
  • a base for instance potassium carbonate, caesium carbonate, sodium hydride or potassium tert-butoxide.
  • the bases dimethylformamide and caesium carbonate are preferably used.
  • the compounds of formula (I) may be purified via common purification procedures, for example by recrystallization or chromatography.
  • the starting materials for the preparation of the compounds of formula (I) are commercially available or may be prepared in accordance with or analogously to literature procedures.
  • the compounds obtained via the abovementioned synthetic methods constitute an additional subject of the present invention.
  • the products that are the subject of the present invention are endowed with advantageous pharmacological properties: it has been found that they especially have inhibitory properties on protein kinases.
  • protein kinases mention is especially made of IGF1R.
  • the products of formula (I) may also be used in the veterinary field.
  • One subject of the invention is thus, as medicinal products, the products of formula (I) as defined above, and also prodrugs thereof, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).
  • a subject of the invention is thus the use, as medicinal products, of the products of formula (Ia), (Ib), (Ic) or (Id) as defined above, and also prodrugs thereof, the said products of formula (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ia), (Ib), (Ic) or (Id).
  • a subject of the invention is thus, most particularly, the use, as medicinal products, of the products of formula (I), the names of which are given hereinbelow:
  • a subject of the invention is thus, most particularly, the use, as medicinal products, of the products of formula (I), the names of which are given hereinbelow:
  • the products may be administered via the parenteral, buccal, perlingual, rectal or topical route.
  • a subject of the invention is thus pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicinal products of formula (I) as defined above.
  • compositions may be in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions.
  • These pharmaceutical forms are prepared according to the usual methods.
  • the active principle may be incorporated into excipients usually used in these compositions, such as aqueous or nonaqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preserving agents.
  • the usual dose which varies according to the individual treated and the complaint under consideration, may be, for example, from 10 mg to 500 mg per day orally in man.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of medicinal products for inhibiting the activity of protein kinases and especially of a protein kinase.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is a protein tyrosine kinase.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is chosen from the following group:
  • protein kinase is chosen from the following group:
  • the present invention thus relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is IGF1R.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is FAK.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is AKT.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is in a cell culture, and also to this use in a mammal.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease characterized by deregulation of the activity of a protein kinase and especially such a disease in a mammal.
  • the present invention relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related macula degeneration, oncology diseases and cancer.
  • a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for treating oncology diseases.
  • the present invention relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for treating cancers.
  • the present invention is most particularly of interest in the treatment of solid tumours and the treatment of cancers that are resistant to cytotoxic agents.
  • the present invention relates most particularly to the treatment of breast cancer, stomach cancer, cancer of the colon, lung cancer, cancer of the ovaries, cancer of the uterus, brain cancer, cancer of the kidney, cancer of the larynx, cancer of the lymphatic system, cancer of the thyroid, cancer of the urogenital tract, cancer of the tract including the seminal vesicle and prostate, bone cancer, cancer of the pancreas and melanomas.
  • the present invention is even more particularly of interest in treating breast cancer, cancer of the colon and lung cancer.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for cancer chemotherapy.
  • the products of formula (I) according to the present invention may be used alone or in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents.
  • the present invention thus relates especially to the pharmaceutical compositions as defined above, characterized in that they are used as medicinal products, in particular for cancer chemotherapy.
  • the present invention thus relates especially to the pharmaceutical compositions as defined above containing, in addition to the active principles, other chemotherapy medicinal products for combating cancer.
  • Such therapeutic agents may be commonly used antitumour agents.
  • inhibitors of protein kinases mention may be made especially of butyrolactone, flavopiridol, 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, olomucine, Glivec and Iressa.
  • the products of formula (I) according to the present invention may thus also be advantageously used in combination with antiproliferative agents: as examples of such antiproliferative agents, but without, however, being limited to this list, mention may be made of aromatase inhibitors, antioestrogens, the topoisomerase I inhibitors, the topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that reduce the activity of protein kinases and also anti-angiogenic compounds, gonadorelin agonists, antiandrogens, bengamides, biphosphonates and trastuzumab.
  • antiproliferative agents examples of such antiproliferative agents, but without, however, being limited to this list, mention may be made of aromatase inhibitors, antioestrogens
  • anti-microtubule agents for instance taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, DNA-intercalating agents, for instance cis-platinum, agents that are interactive on topoisomerase, for instance camptothecin and derivatives, anthracyclines, for instance adriamycin, antimetabolites, for instance 5-fluorouracil and derivatives, and the like.
  • the present invention thus relates to products of formula (I) as protein kinase inhibitors, the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts of the said products of formula (I) with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases, and also the prodrugs thereof.
  • the present invention relates particularly to products of formula (I) as defined above as IGF1R inhibitors.
  • the present invention also relates to products of formula (I) as defined above as FAK inhibitors.
  • the present invention also relates to products of formula (I) as defined above as AKT inhibitors.
  • the present invention relates more particularly to the products of formula (Ia), (Ib), (Ic) and in particular (Id) as defined above as IGF1R inhibitors.
  • Example 1c 3-(3-amino-4-trifluormethoxy-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 1d N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-chloro-acetamide
  • Example 1e N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-morpholin-4-yl-acetamide
  • Example 8 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4-methyl-piperazin-1-yl)-acetamide trifluoroacetate
  • Example 12 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-[(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate
  • Example 13 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2-hydroxy-ethylamino)-acetamide trifluoroacetate
  • Example 17 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4-methyl-piperidin-1-yl)-acetamide
  • Example 18 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4-methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate
  • Example 20 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(1,2,2-trimethyl-propylamino)-acetamide trifluoroacetate
  • Example 21 ( ⁇ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenylcarbamoyl]-methyl ⁇ -amino)-acetic acid methyl ester; compound with trifluoro-acetic acid
  • Example 26 1- ⁇ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenylcarbamoyl]-methyl ⁇ -pyrrolidine-3-carboxylic acid methyl ester
  • Example 30 ( ⁇ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenylcarbamoyl]-methyl ⁇ -amino)-acetic acid trifluoroacetate
  • Example 33a N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-acrylamide
  • Example 33b N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-morpholin-4-yl-propionamide trifluoroacetate
  • Example 34 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidia-1-yl)-2-trifluoromethoxy- phenyl]-3-(dimethyl-morpholin-4-yl)-propionamide trifluoroacetate
  • Example 35 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(4-methyl-piperazin-1-yl)-propionamide trifluoroacetate
  • Example 36 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-piperidin-1-yl-propionamide trifluoroacetate
  • Example 37 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-thiomorpholin-4-yl-propionamide trifluoroacetate
  • Example 38 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-pyrrolidin-1-yl-propionamide trifluoroacetate
  • Example 40 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(2,2,2-trifluoro-ethylamino)-propionamide, compound with trifluoro-acetic acid
  • Example 42c 3-(3-amino-4-isopropyl-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 42d N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloroacetamide
  • Example 42e N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-l-yl)-2-isopropyl-phenyl]-2-morpholin-4-yl-acetamide trifluoroacetate
  • Example 48 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)- 2-isopropyl-phenyl]-acetamide trifluoroacetate
  • Example 49 1-Methyl-piperidine-4-carboxylic acid [5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-amide, trifluoro-acetate
  • Example 50 1-Methyl-piperidine-3-carboxylic acid [5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl-2-trifluoromethoxy-phenyl]-amide, compound with trifluoro-acetic acid
  • Example 51c 3-[3-(2,2-Diethoxy-ethoxy)-4-methoxyphenyl]-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 51e 3-[4-Methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 54 3- ⁇ 4-Methoxy-3-[2-(2-methoxy-ethylamino)-ethoxy]-phenyl ⁇ -5,5-dimethyl-1-quinolin-4- ylmethyl-imidazolidine-2,4-dione
  • Example 56 3-(4-Methoxy-3- ⁇ 2-[(5-methyl-isoxazol-3-ylmethyl)-amino]-ethoxy ⁇ -phenyl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 60 3- ⁇ 4-Methoxy-3-[2-(2-pyridin-4-yl-ethylamino)-ethoxy]-phenyl ⁇ -5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 64 3-(4-Methoxy-3- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethoxy ⁇ -phenyl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 65 3-(4-Methoxy-3- ⁇ 2-[(thiazol-2-ylmethyl)-amino]-ethoxy ⁇ -phenyl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 70 3- ⁇ 4-Methoxy-3-[2-(1-methyl-piperidin-4-ylamino)-ethoxy]-phenyl ⁇ -5,5-dimethyl-1-quinolin- 4-ylmethyl-imidazolidine-2,4-dione
  • the title compound was prepared in analogy to example 51e by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-acetaldehyde as starting material and 4-amino-1-methylpiperidine instead of morpholine.
  • the title compound was prepared in analogy to example 51e by using 70 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-acetaldehyde as starting material and 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester instead of morpholine.
  • the product was obtained as its trifluoroacetate salt.
  • Example 71a 3- ⁇ 4-Methoxy-3-[2-(pyrrolidin-3-ylamino)-ethoxy]-phenyl ⁇ -5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • Example 72 3- ⁇ 3-[2-Hydroxy-3-(tetrahydro-pyran-4-ylamino)-propoxyl-4-methoxy-phenyl ⁇ -5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione
  • the following compound was prepared in analogy to example 72 by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-acetaldehyde as starting material and pyridin-4-yl-methylamine instead of tetrahydro-pyran-4-ylamine.
  • the product was obtained as its trifluoroacetate salt.
  • the following compound was prepared in analogy to example 72 by using 4-amino-1-methyl-piperidine instead of tetrahydro-pyran-4-ylamine.
  • the crude product was purified in addition by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid.
  • the following compound was prepared in analogy to example 72 by using 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester instead of tetrahydro-pyran-4-ylamine.
  • the crude product was dissolved in 2 ml of a 8 N solution of hydrochloric acid in methanol and the resulting solution was stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was dissolved in a mixture of 2 ml water and 1 ml acetonitrile. After lyophilisation of the solution the residue was purified in addition by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid).
  • 1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone was prepared according to a procedure published by Daniel Elbaum et al. Patent Application US 6114365.
  • the title compound was prepared in analogy to example 51c by using 100 mg 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone instead of 2-amino-thiazole-5-carboxylic acid methyl ester.
  • UV data have been recorded at 220 nm and at 254 nm.
  • H2O+0.05% TFA and ACN+ 0.05% TFA are mixed in 95:5 (0 min) to 5:95 (3.4 min) to 5:95 (4.4 min) ratios at a flow rate of 1 ml min-1.
  • Tablets corresponding to the following formula were prepared: Product of Example 9 0.2 g Excipient for a finished tablet weighing 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).
  • Tablets corresponding to the following formula were prepared: Product of Example 32......................... 0.2 g Excipient for a finished tablet weighing 7-8 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).
  • the examples of pharmaceutical compositions 81 and 82 above illustrate the present invention, it being understood that the same preparations may be made with other preferred products of the present invention and form part of the present invention.

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EP04291904A 2004-07-27 2004-07-27 Dérivés d'urées cycliques aminés, leur préparation et utilisation pharmaceutique en tant qu'inhibiteurs de Kinase Withdrawn EP1621536A1 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
EP04291904A EP1621536A1 (fr) 2004-07-27 2004-07-27 Dérivés d'urées cycliques aminés, leur préparation et utilisation pharmaceutique en tant qu'inhibiteurs de Kinase
PE2005000866A PE20060383A1 (es) 2004-07-27 2005-07-25 Nuevos derivados amino de urea ciclicos como inhibidores de quinasa
JP2007523038A JP2008508228A (ja) 2004-07-27 2005-07-25 新規アミノ環状尿素誘導体、その調製及びキナーゼ阻害剤としてのその薬学的使用
KR1020077002102A KR20070038529A (ko) 2004-07-27 2005-07-25 신규한 시클릭 우레아 유도체, 그의 제조 방법 및 그의키나제 억제제로서의 제약적 용도
PCT/EP2005/008720 WO2006010641A2 (fr) 2004-07-27 2005-07-25 Nouveaux derives d'uree cyclique, leur preparation, et leur utilisation pharmaceutique comme inhibiteurs de la kinase
BRPI0512681-9A BRPI0512681A (pt) 2004-07-27 2005-07-25 derivados de uréia cìclica de amino, preparação destes e emprego farmacêutico destes como inibidores de cinase
AU2005266460A AU2005266460A1 (en) 2004-07-27 2005-07-25 Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
EA200700141A EA011088B1 (ru) 2004-07-27 2005-07-25 Новые аминоциклические производные мочевины, их получение и фармацевтическое применение в качестве ингибиторов киназы
CA002571323A CA2571323A1 (fr) 2004-07-27 2005-07-25 Nouveaux derives d'uree cyclique, leur preparation, et leur utilisation pharmaceutique comme inhibiteurs de la kinase
AT05771072T ATE498618T1 (de) 2004-07-27 2005-07-25 Neue zyklische harnstoffderivate, deren herstellung und pharmazeutische verwendung damit als kinase-inhibitoren
MX2007001024A MX2007001024A (es) 2004-07-27 2005-07-25 Nuevos derivados amino de urea ciclicos, su preparacion y su uso farmaceutico como inhibidores de quinasa.
CNA2005800250805A CN101031559A (zh) 2004-07-27 2005-07-25 氨基环脲衍生物和其制法及作为激酶抑制剂的医药用途
EP05771072A EP1773808B1 (fr) 2004-07-27 2005-07-25 Nouveaux derives d'uree cyclique, leur preparation, et leur utilisation pharmaceutique comme inhibiteurs de la kinase
DE602005026395T DE602005026395D1 (de) 2004-07-27 2005-07-25 Neue zyklische harnstoffderivate, deren herstellung und pharmazeutische verwendung damit als kinase-inhibitoren
ARP050103075A AR050269A1 (es) 2004-07-27 2005-07-25 Derivados amino de urea ciclicos, su preparacion y su uso farmaceutico como inhibidores de quinasa
TW094125192A TW200616973A (en) 2004-07-27 2005-07-26 Novel amino cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
UY29039A UY29039A1 (es) 2004-07-27 2005-07-27 Nuevos derivados amino de urea cíclicos, su preparación y su uso farmacéutico como inhibidores de quinasa
IL180286A IL180286A0 (en) 2004-07-27 2006-12-24 Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
MA29602A MA28732B1 (fr) 2004-07-27 2007-01-02 Nouveaux derives d'uree cyclique, leur preparation, et leur uttilisation pharmaceutique comme inhibiteurs de la kinase
US11/627,518 US7759379B2 (en) 2004-07-27 2007-01-26 Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
NO20071067A NO20071067L (no) 2004-07-27 2007-02-26 Nye cykliske ureaderivater, fremstilling derav og farmasoytisk anvendelse derav som kinaseinhibitorer.

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EP04291904A EP1621536A1 (fr) 2004-07-27 2004-07-27 Dérivés d'urées cycliques aminés, leur préparation et utilisation pharmaceutique en tant qu'inhibiteurs de Kinase

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EP05771072A Expired - Lifetime EP1773808B1 (fr) 2004-07-27 2005-07-25 Nouveaux derives d'uree cyclique, leur preparation, et leur utilisation pharmaceutique comme inhibiteurs de la kinase

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US (1) US7759379B2 (fr)
EP (2) EP1621536A1 (fr)
JP (1) JP2008508228A (fr)
KR (1) KR20070038529A (fr)
CN (1) CN101031559A (fr)
AR (1) AR050269A1 (fr)
AT (1) ATE498618T1 (fr)
AU (1) AU2005266460A1 (fr)
BR (1) BRPI0512681A (fr)
CA (1) CA2571323A1 (fr)
DE (1) DE602005026395D1 (fr)
EA (1) EA011088B1 (fr)
IL (1) IL180286A0 (fr)
MA (1) MA28732B1 (fr)
MX (1) MX2007001024A (fr)
NO (1) NO20071067L (fr)
PE (1) PE20060383A1 (fr)
TW (1) TW200616973A (fr)
UY (1) UY29039A1 (fr)
WO (1) WO2006010641A2 (fr)

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JP2008508228A (ja) 2008-03-21
EA011088B1 (ru) 2008-12-30
NO20071067L (no) 2007-04-26
EP1773808A2 (fr) 2007-04-18
PE20060383A1 (es) 2006-06-06
MX2007001024A (es) 2007-04-16
ATE498618T1 (de) 2011-03-15
US20080004300A1 (en) 2008-01-03
KR20070038529A (ko) 2007-04-10
TW200616973A (en) 2006-06-01
WO2006010641A2 (fr) 2006-02-02
WO2006010641A3 (fr) 2006-10-26
IL180286A0 (en) 2007-07-04
CA2571323A1 (fr) 2006-01-02
EA200700141A1 (ru) 2007-08-31
AR050269A1 (es) 2006-10-11
MA28732B1 (fr) 2007-07-02
US7759379B2 (en) 2010-07-20
EP1773808B1 (fr) 2011-02-16
AU2005266460A1 (en) 2006-02-02
CN101031559A (zh) 2007-09-05
DE602005026395D1 (de) 2011-03-31
BRPI0512681A (pt) 2008-04-01
UY29039A1 (es) 2006-02-24

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